Apparatus designed to modulate the neurovegetative system and integrate its action with that of the central nervous system; applications in the treatment of the vascular system and orthopaedic disorders

ABSTRACT

This invention relates to a new type of apparatus designed to modulate the neurovegetative system and integrate the neurovegetative action with that of the central nervous system. The method is not invasive, because it uses pulses transmitted through the skin; the intensity of the stimulus is controlled directly by the patient in order to achieve better integration with the central nervous system. This invention effectively treats vascular disorders resulting from obstruction of the arteries of the legs, heart and brain because it induces vasodilatation and increases blood flow and the production of new blood vessels. The method also improves lesions of the spinal column, especially those affecting the back and neck, and other orthopaedic disorders.

This application is the US national phase of international applicationPCT/EP01/08756 filed 27 Jul. 2001, which designated the US.

FIELD OF THE INVENTION

This invention relates to apparatus and an innovative method designed toregulate the function of the neurovegetative system and integrate itwith that of the central nervous system. This effect is achieved byadministering electrical pulses to the skin, the intensity of the pulsesbeing controlled directly by the patient.

The new method induces vasodilatation, stimulates neoangiogenesis andincreases blood flow. The regulation of the vascular flow obtained withthe new technology allows treatment of vascular diseases involvingorganic obstruction of the arteries, which often affect the lower limbs,heart and brain. The new technology also allows effective treatment ofdisorders of the spinal column, especially the neck and the lumbosacralarea.

The same apparatus can be effectively used to treat many otherorthopaedic disorders, for example inflammation and proprioceptivesensory alterations caused by damage to the muscolar and articularsystem.

BACKGROUND OF THE INVENTION

Atherosclerosis and thrombosis are frequent causes of arterialobstruction.

Atherosclerosis is responsible for most cases of arterial occlusionaffecting the myocardium, brain and peripheral arteries.

Arterial obstruction or narrowing causes a reduction in blood floweither during exercise or at rest. The clinical signs result fromischaemia. The atherosclerotic lesions which affect large and smallblood vessels in diabetics are very similar to those which appear innon-diabetics; however, they appear earlier, worsen more quickly and aremore frequent in the case of diabetics.

Distal arterial occlusion below the knee together with microvascularalterations and neurological lesions are responsible for gangrene. Thesymptoms are intermittent claudication and pain at rest caused byischaemia. Diabetic foot, which is caused by a combination ofvasculopathy, neuropathy and infection, is one of the most dangerouscomplications of diabetes, and is the cause of most amputations.Amputation of the foot or leg is five times as frequent in diabetics asin non-diabetics. Angina and myocardial infarction are the most frequentcomplications of occlusion or stenosis of the coronary artery.

These local actions, together with those of the autonomic nervous systemand the vascular system, cause vasoconstriction when activated, such asafter exposure to cold; conversely, a reduction in these effects resultsin vasodilatation.

The development of collateral circulation which results from stenosis ora major obstruction of the arteries influences the degree of ischaemia.Some collateral vessels are present in normal tissue, but do not dilateuntil arterial obstruction appears, while other capillaries develop inweeks or months. The adrenergic nerves, which are part of the autonomicnervous system, are responsible for vasoconstriction or dilatation ofthe collateral vessels in response to the increase in arterial pressure,with the result that the flow of blood to the tissue is improved.

Substances produced by the endothelial cells which induce new bloodvessel formation (neoangiogenesis) and vasodilatation were recentlydiscovered. The production of VEGF (Vascular Endothelial Growth Factor),which seems to be responsible for the majority of the angiogenic and`vasodilatory effect that results from stenosis or arterial obstruction,appears to be particularly important.

Experiments with isolated animal muscles have demonstrated thatcontinuous electrical stimulation for 5 days (stimulation of 0.3 ms ofamplitude, frequency of 150 Hz and voltage of 0.1 V) increases VEGFproduction, the number of capillaries and the blood flow (Kanno S, OdamAbe M. Circulation 1999; 99, 2682-87).

Although the experiments described above seem to suggest that electricalstimulation of the muscles has beneficial effects on the circulation,the problem remains of how to induce a prolonged stimulation on nervesand muscles in humans.

Patients suffering from acute ischaemia or initial infarction presentincreased production of VEGF in the myocardium and in the endothelialcells of the capillaries and arterioles (Lee S H, Wolf P L, Escudero R,N. Engi. J. Med. 2000; 342, 626-33).

The revascularisation induced by a transmyocardial laser with the aim ofreducing angina pain is accompanied by an increase in VEGF andangiogenesis (Horvath, Chiu E, Maun A C, Annals of Thoracic Surgery1999; 68, 825-29).

Modern technology offers some highly sophisticated instruments whichallow the use of new techniques such as transmyocardial laserrevascularisation, but the results are still limited. An electricalphoryngeal neuromuscolar stimulator is disclosed in WO 99/24111.

The treatment of peripheral vascular disease is usually unsatisfactory.Vasodilators have a modest effect, and sympathectomy is ineffective. Theinjection of VEGF produced by GMO (Genetically Modified Organisms) isnot without side effects. The only therapeutic solution is vascularsurgery.

In practice, no really effective system for the treatment of peripheralvascular disorders has yet been found. Vasodilators give poor results,treatment with VEGF based on recombinant DNA is not safe enough, andeven surgery is just one of the various alternatives, which has notdemonstrated any real efficacy.

BRIEF SUMMARY OF THE INVENTION

The present invention proposes an apparatus for the treatment ofischaemic disease which can generate and apply a series of controlledpulses designed to stimulate the patient and elicit an effectiveresponse, which eliminates inflammation from the part of the bodytreated, activates the peripheral microcirculation and stimulates VEGFproduction.

The apparatus in accordance with the invention uses a non-invasivetechnique, because the stimulus is transmitted transcutaneously by meansof electrodes.

The signals emitted by the machine are sent to the vascular receptorswhere they induce vasodilatation and stimulate VEGF release.

Using the apparatus in accordance with the invention, ischaemia can betreated and ischaemic pain reduced.

The invention is based on a series of studies conducted by theapplicants which demonstrate that by applying a series of electricalpulses to the patient, a biochemical response can be induced which notonly eliminates inflammation from the part of the body treated andreduces or eliminates pain, but also has a rapid muscle-relaxant effect,and stimulates vasodilatation and VEGF production.

However, the apparatus must also detect the response of the tissues toelectrical stimulation and vary the stimulation parameters to obtain thedesired result.

For this purpose, the apparatus to which the invention relates generateselectrical pulses whose variables activate the patient'sneurophysiological control systems.

The pulse parameters are defined on the basis of the bioreaction of thetissues. The intensity of the pulse is directly regulated by thepatient, according to preset treatment programs.

After establishing experimentally that the apparatus in accordance withthe invention produces excellent results with muscle relaxation, theinventors formulated the hypothesis that the same apparatus mighteffectively induce vasodilatation and stimulate VEGF production.

Subsequent experiments demonstrated that this hypothesis waswell-founded, and that the apparatus to which the invention relatesproduces the postulated results.

The apparatus according to the invention comprises:

-   -   means designed to generate electrical pulse series having a        width from 10 to 40 μsec and intensity from 100 to 170 μAmp,        wherein each pulse has a peak that has a width from 7 to 12        nanosec. and a voltage up to 220 Volts;    -   means designed to apply the said pulses to a patient through the        epidermis;    -   means designed to evaluate the tissue reaction;    -   means designed to vary the said pulses on the basis of the        tissue reaction detected;        at least one of which means can be controlled by the        patient/user.

The invention also provides a method of the treatment of vascular and/ormuscle and/or tendon disorders, comprising:

-   -   a) applying to a patient in need thereof, a series of electrical        pulses having a width from 10 to 40 μsec and intensity from 100        to 170 μAmp, wherein each pulse has a peak that has a width from        7 to 12 nanosec. and a voltage up to 220 Volts through        electrodes located on the epidermis of the area to be treated;    -   b) detecting the tissue reaction after the application of the        pulses;    -   c) modifying the width and intensity of the pulses in relation        to the tissue reaction detected in point b).

The invention also provides a method for increasing the VEGF in apatient in need thereof, comprising:

-   -   a) applying to a patient in need thereof, a series of electrical        pulses having a width from 10 to 40 μsec and intensity from 100        to 170 μAmp, wherein each pulse has a peak that has a width from        7 to 12 nanosec. and a voltage up to 220 Volts through        electrodes located on the epidermis of the area to be treated;    -   b) detecting the tissue reaction after the application of the        pulses;    -   c) modifying the width and intensity of the pulses in relation        to the tissue reaction detected in point b).

Advantages features of the apparatus of the invention are stated in theannexed dependent claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

One embodiment of the apparatus is illustrated in the attached figures,in which:

FIG. 1 is a block diagram of the apparatus in accordance with theinvention

FIG. 2 is the circuit diagram of the forward/back selector switch in thecircuit shown in FIG. 1

FIG. 3 is the circuit diagram of the selector switch-counter logicnetwork of the circuit shown in FIG. 1

FIG. 4 is a diagram of the up/down circuits, +DAC

FIG. 5 is the circuit diagram of the output stage of the circuit shownin FIG. 1

FIG. 6 is the circuit diagram of the timer in the circuit shown in FIG.1

FIG. 7 is the circuit diagram of the automatic pulse train widthregulator in the circuit shown in FIG. 1

FIG. 8 is the circuit diagram of the frequency regulator and timer inthe circuit shown in FIG. 1

FIG. 9 is the circuit diagram of the control activated by the patient inthe circuit shown in FIG. 1;

FIG. 10 shows the oscilloscopic trace of a pulse which shows a peakhaving a width of 10 nanosec.

FIG. 11 shows the waveform displayed by an oscilloscope, of the pulse ofFIG. 10, over a total time of 100 nanosec.;

FIG. 12 is an expanded view of the peak of the pulse of FIG. 11.

DETAILED DESCRIPTION OF THE INVENTION

The circuits illustrated in the figures do not require a more detailedexplanation because the information obtainable from the drawings issufficient to allow an expert in the field to implement the invention.

The apparatus includes devices which generate and regulate a series ofelectrical pulses that are sent to a pair of electrodes at the output,and is fitted with a control which allows the patient to regulate atleast one of the control parameters of the said pulses, especially thevoltage, according to preset treatment programs correlating the detectedbioreaction to the time, frequency and width of the electrical pulses.

The electrodes, one active and one passive (or reference) electrode, areapplied in different positions, depending on the tissue treated.

These regulations can be performed by means of an ordinary controlfitted with pushbuttons and/or potentiometers which is activated by thepatient.

The circuit shown in FIG. 2 allows forward/back regulation, in that itallows the patient to select an increased or reduced voltage, while thecircuit shown in FIG. 3 is a counting circuit which counts the number ofsteps set with the control, in order to calculate the extent of thevariation to be imparted to the output voltage signal.

In particular, the amount of this voltage variation is between 0.47 and0.63 volts.

The digital count signal output from circuit 3 is then converted into ananalog signal in the circuit shown in FIG. 4, where the pulse trains aregenerated; they then pass to the output stage shown in FIG. 5 afterbeing suitably regulated by the circuits shown in FIGS. 6, 7 and 8.

The circuits shown in FIGS. 6 and 7 regulate the duration (width) of thepulses and the increase in width between two successive pulse trains.

The circuit shown in FIG. 8 is the timer which determines the durationof the pulse train, while FIG. 9 shows the circuit diagram of thecontrol activated by the patient.

During the initial stage of the experiments, the apparatus was regulatedso as to generate a series of pulses with a voltage of approx. 80 volts,the width of each pulse being selectable between 10 and 90 microseconds,and the frequency being selectable between 1 and 999 pulses a second.

The electrodes at the output of the apparatus were applied to theepidermis at the area to be treated, one to the motor point and theother to the muscle belly.

The tests were performed by effecting treatments of differentfrequencies ranging from 1 to 420 pulses a second, and different widths,ranging from 10 to 50 microseconds, for a total time of 10 to 15minutes.

120 patients suffering from orthopaedic disorders whose main componentwas local ischaemia or inflammation were treated.

The results demonstrated good vascularisation of the tissues, but therewas no significant improvement in the inflammation.

The pulses were checked with an oscilloscope, which showed that thepulse in contact with the skin underwent considerable deformation, andthe patient developed evident tolerance after only 3 minutes.

During a second series of tests, the machine was set to vary the widthof the pulses after each series of pulses applied in the same cycle, inorder to prevent tolerance by the patient and deformation of the pulses.

300 patients suffering from orthopaedic disorders complicated byinflammation and ischaemia were treated by applying several series ofpulses and increasing the pulse width from time to time during the sametreatment.

The results demonstrated that reduction of inflammation and improvementin blood flow were associated with modulation of the neurovegetativenervous system.

A further test was then conducted with 120 patients suffering fromorthopaedic disorders associated with inflammation or deficiency of thelocal microcirculation.

The treatment comprised 12 ten-minute sessions in which electrodes wereapplied to the epidermis at a distance of approx. 10-15 centimetresapart.

The patient could increase or decrease the voltage of the pulse duringstimulation with a remote control.

The variation in intensity of the pulse voluntarily decided on by thepatient and the variation in the physiological bioreaction time ormuscle relaxation times were observed simultaneously with a double-traceoscilloscope.

These first tests confirmed the inventor's intuition, namely that theapplication of series of electrical pulses under given voltage,frequency and width conditions could produce the desired results.

The following examples and tables show the results of further, moredetailed tests.

EXAMPLE 1

Muscle Relaxation (Tables 1a-d and 2)

With the machine in accordance with the invention, one electrode wasapplied to the motor point and one to the belly of the trapezius muscle,and pulse trains were sent to the patient for 30 seconds at a voltage ofapprox. 180 volts, with a frequency of one pulse a second and a width of10 microseconds.

During the second phase, lasting 5 seconds, the pulses were applied atthe frequency of one a second, with a width of 20 microseconds.

As the test continued, the parameters were varied from time to time asindicated in the annexed tables 1a to 1d until the muscle reached spasm,then relaxed and remained in that condition.

As will be seen from the graph in Table 2, after approx. 12 phases oftreatment the muscle reached an almost permanent state of relaxation.

This relaxation corresponds to the maximum degree of vascularisation andthe maximum anti-inflammatory effect.

The anti-inflammatory treatment programme is shown in Table 3 and theassociated Graph 4.

Table 5 and the associated graph 6 show a treatment programme foractivation of the microcirculation.

The details set out above demonstrate that the apparatus in accordancewith the invention is able to relax the muscles, induce vasodilatation,increase the blood flow and stimulate new vessel production.

The technique is non-invasive because the signal is transmittedtranscutaneously through electrodes.

The signals emitted with this new technology are conducted by thesensory and proprioceptive fibres of the autonomic nervous system, andreach the vascular and muscle receptors through which vasodilatation andmuscle relaxation is produced; the blood flow is increased and VEGFrelease is stimulated.

The treatment combats ischaemia and reduces pain. The clinical symptomsof ischaemia, such as claudication due to contraction of the calf, thighor buttocks and pain at rest, rapidly regress, and the patient walksnormally.

Vasodilatation and increased blood flow take place in all parts of thebody to which the treatment is applied. The effect is long-lasting;however, its duration depends on the degree of arterial obstruction andthe time taken for collateral circulation to develop. Measurements takenwith a laser doppler demonstrate significant increases in blood flow inthe treated areas.

The efficacy of the treatment is demonstrated by the following example.

EXAMPLE 2

12 patients with distal arterial occlusion (7 with occlusion of thetibial artery and 5 with occlusion of the femoral artery) were studiedbefore, during and after stimulation with the new technology.

The VEGF (pg/ml) was assayed at the times shown in FIG. 10.

As will be seen, an increase in VEGF was already evident 2-3 minutesafter the start of the stimulus; it peaked after 5 mins (the increasewas approx. 50%), and returned to normal after 15 mins.

Further tests confirmed that the best results can be obtained withseries of pulses having a width from 10 to 40 μsec. and an intensityfrom 100 to 170 μAmp., with a peak having a width from 7 to 12 nanosec.and a voltage up to 220 Volts.

The waveform of a pulse of this kind, as displayed by an oscilloscope,is shown in FIGS. 10-12.

These data demonstrate for the first time that the application of theinvention is able to increase VEGF, the most potent specific endogenousangiogenic factor identified to date. Increased VEGF production was alsoaccompanied by vasodilatation. By contrast with what happens inlaboratory animals subjected to a direct stimulus on the isolated muscleand nerve, this method enables the stimulus to be induced through theskin with electrodes. The time taken to stimulate VEGF is a few minutes,whereas the electrical stimulation used in animals takes days to achievethe same result. In the case of severe stenosis or arterial obstruction,recurrence of the ischaemia symptoms after suspension of the treatmentis often due to a deficiency in the development of collateralcirculation. In this case the treatment must be continued or an arterialbypass performed, which may be followed by new treatment to ensurecomplete healing of the tissues.

Maintenance of a high blood flow in the treated tissues increases thetrophism of the tissue, prevents necrosis and heals ulcers.

The application of this invention to specific parts of the body ratherthan directly to the heart induces coronary vasodilatation and increasesVEGF production in the coronary sinus.

This effect has been observed in 3 patients who underwent cardiaccatheterisation, from whom blood samples were taken at the same time toassay the cardiac VEGF.

The treatment can also be applied to lesions of the spinal column andpain syndromes of the back and neck.

The spinal column, together with the spinal cord, nerve roots, spinalligaments and paraspinal muscles are the sites of some of the mostfrequent disorders to which human beings are liable. The cervical andlumbar pain which originates in these structures affects nearly everyonesooner or later. This disorder, together with alcoholism, is one of themajor causes of absenteeism.

The most important symptom of lesions of the spinal column and thevarious structures that compose it is pain, which may be local ormuscle-related. Pain is caused by irritation of the nerve ending at thesite of the pathological process. Treatment of patients with cervicaland back pain is very difficult, and often ineffective. Rest, combinedwith analgesics, is currently considered to be the best treatment.Physiotherapy is performed with the aim of strengthening theparavertebral muscles to prevent painful relapses. Neck manipulation ispotentially dangerous. This invention provides an innovative approach tothe treatment of lesions of the spinal column.

As mentioned, this new technology acts through the autonomic nervoussystem, targeting the structures of the spinal column which are mostoften affected by painful disorders, such as the ligaments, periosteumand paravertebral muscles, by acting on the muscle spindles, the Golgitendon organs and the joint proprioceptors. Its action is followed by areduction in oedema, inflammation and pain.

This treatment has been tested on some 200 patients suffering fromcervical or lumbar pain.

Most of the patients felt better within a few days (3-10). 60 of themhad a slipped disc; 10 of them had already been operated on for slippeddisc but still felt pain. The treatment was effective in 92% of cases.90% of the patients suffering from slipped disc did not need anoperation because the compression or inflammation symptoms of the nerveroot were eliminated by the treatment.

The results obtained with this method demonstrate that the technique hasmultiple effects on mechanical lesions of the spinal column and theircomplications:

it eliminates pain and returns the proprioceptive sensitivity to normal

it restores normal muscle contractility

it eliminates inflammation.

The same technology has been tested in other disorders.

For example, the invention has been successfully tested in the treatmentof numerous other disorders such as cervical, back, hip, thigh and kneepain, knee instability, Achilles tendinitis, calcaneal spur,metatarsalgia, and shoulder, elbow, wrist and hand disorders.

In conclusion, the new treatment improves the quality of life andreduces one of the most frequent causes of absenteeism.

1. Apparatus for the treatment of vascular and/or muscle and/or tendondisorders and/or to increase the production of Vascular EndothelialGrowth Factor (VEGF), and/or for anti-inflammatory treatment and/or forthe activation of the microcirculation, comprising: means designed togenerate electrical pulse series having a width from 10 to 40 μsec andintensity from 100 to 170 μAmp, wherein each pulse has a peak that has awidth from 7 to 12 nanosec. and a voltage up to 220 Volts; meansdesigned to apply the said pulses to a patient through the epidermis;means designed to evaluate the tissue reaction; means designed to varythe said pulses on the basis of the tissue reaction detected; at leastone of which means can be controlled by the patient/user.
 2. Apparatusfor the treatment of vascular and/or muscle and/or tendon disorders asclaimed in claim
 1. 3. Apparatus as claimed in claim 1, wherein thevoltage of the pulses applied is controlled by the patient/user bysuitable means.
 4. Apparatus as claimed in claim 1, characterised inthat it includes a pair of electrodes designed to transmit the saidpulses, one of which can be applied to the motor point and the other tothe muscle belly in the area to be treated.
 5. Apparatus as claimed inclaim 1, characterised in that the said means designed to apply the saidpulses include devices able to vary the voltage, amplitude and frequencyof the said pulses.
 6. Apparatus as claimed in claim 1, characterised inthat it includes means designed to regulate the amplitude and frequencyof the pulses, which said means are activated directly by the patient.7. Apparatus for the treatment of muscle contraction as claimed in claim1, characterised in that it includes a pair of electrodes designed totransmit the said pulses, one of which can be applied to the motor pointand the other to the muscle belly in the area to be treated. 8.Apparatus for anti-inflammatory treatment as claimed in claim 1,characterised in that it includes an active electrode designed to beapplied at the site of inflammation, and a passive electrode external tothe said site.
 9. Apparatus for the treatment of vascular disorders asclaimed in claim 1, characterised in that it includes an activeelectrode designed to be applied upstream of the occlusion and a passiveelectrode designed to be applied downstream thereof.
 10. Apparatus forthe activation of the microcirculation as claimed in claim 1,characterised in that it includes an active electrode designed to beapplied to the ischaemic site and a passive electrode designed to beapplied close to the venous plexus.
 11. Apparatus as claimed in claim 1,characterised in that it includes means designed to vary the voltage ofthe pulses applied, with variable increments between 0.47 V and 0.63 Vfor each step of an up/down circuit which allows the user to select anincreased or reduced voltage.
 12. Apparatus as claimed in claim 1,characterised in that it includes means designed to vary the number ofpulses applied between 1 and 420 pulses/second.
 13. Apparatus as claimedin claim 1, characterized in that it includes means designed to vary thewidth of the pulses between 10 and 50 μsec.
 14. A method of thetreatment of vascular and/or muscle and/or tendon disorders, comprising:a) applying to a patient in need thereof, a series of electrical pulseshaving a width from 10 to 40 μsec and intensity from 100 to 170 μAmp,wherein each pulse has a peak that has a width from 7 to 12 nanosec. anda voltage up to 220 Volts through electrodes located on the epidermis ofthe area to be treated; b) detecting the tissue reaction after theapplication of the pulses; c) modifying the width and intensity of thepulses in relation to the tissue reaction detected in point b).
 15. Amethod according to claim 14 wherein the pulses are modified accordingto preset treatment programs correlating the detected bioreaction to thetime, frequency and width of the electrical pulses.
 16. A method forincreasing the Vascular Endothelial Growth Factor (VEGF) in a patient inneed thereof, comprising: a) applying to a patient in need thereof, aseries of electrical pulses having a width from 10 to 40 μsec andintensity from 100 to 170 μAmp, wherein each pulse has a peak that has awidth from 7 to 12 nanosec. and a voltage up to 220 Volts throughelectrodes located on the epidermis of the area to be treated; b)detecting the tissue reaction after the application of the pulses; c)modifying the width and intensity of the pulses in relation to thetissue reaction detected in point b).
 17. A method according to claim 16wherein the patient is affected by a combination of vasculopathy andneuropathy.
 18. A method according to claim 17 wherein the patient isaffected by diabetic foot.